The histone acetyltransferase (HAT) enzymes p300 and CBP are closely related paralogs that serve as transcriptional coactivators. The p300 and CBP catalyze the acetylation of Lys residues in histones and other proteins. Serving as transcriptional coactivators, p300 and CBP participate in numerous ways to regulate cell growth, differentiation, and gene expression across many organ systems and physiologic pathways. Dysregulation of p300/CBP by mutation, altered expression, or other mechanisms has been linked to disease states, including various malignancies such as acute leukemias and prostate cancer. Furthermore, p300/CBP is critical in development as evidenced by the genetic disorder Rubinstein-Taybi syndrome, which occurs with loss of function mutations in single alleles of either p300 or CBP.
Inhibitors of p300/CBP HAT activity have been developed and are under investigation as therapeutics for a number of diseases.
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A potent, selective and, cell and in vivo active p300/CBP catalytic inhibitor with IC50 of 9.8/2.6 nM; displays selectivity for p300/CBP over other HATs and histone methyltransferases in cells; dose-dependently decreases H3K27Ac in prostate adenocarcinoma PC-3 cells with EC50 of 73 nM; selectively inhibits proliferation in lineage-specific tumour types; inhibits the AR transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibits tumour growth in a castration-resistant xenograft model.
A specific and potent inhibitor of CBP/p300 bromodomain with Kd of 150-170 nM; displaces H3K56ac from the CBP binding site with an IC50 of 170 nM; demonstrates 37-fold and 132-fold selectivity over BRD4 BD1 and BRD4 BD2, respectively; increases the cytotoxic activity of JQ1 in leukemic cells; impaires the disease-initiating self-renewal leukemic cells in vitro and in vivo without causing significant cytotoxicity.
TTK21 (CBP-p300 activator TTK21) is a small molecule activator of CBP/p300 histone acetyltransferase activity with a maximal effect at a concentration of 275 uM; induces acetylation of histones H3 and H4 in vitro but not H2B and H2A; promotes neurogenesis and extends memory duration in adult mice, promotes regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury.
L-002 (NSC 764414, L002) is a novel potent, specific acetyltransferase p300 (KAT3B) inhibitor with IC50 of 1.98 uM; also shows weak inhibitory activity against PCAF (KAT2B) and GCN5 (KAT2A) with IC50 of 34.7 and 33.9 uM, displays no inhibition against Tip60, MYST2 and MYST4 (IC50>100 uM), as well as a panel of HDACs and HMTs; inhibits acetylation of histones and p53, and suppresses STAT3 activation in cell-based assays; exhibits extreme sensitivity against leukemia, breas and lymphoma cell lines; potently suppresses tumor growth and histone acetylation of MDA-MB-468 xenografts.
CPTH6 is a thiazole derivative that can reduce histone acetylation and histone acetyltransferase (HAT) activity in human leukemia cells, CPTH6 is a specific Gcn5/pCAF inhibitor; CPTH6 exerts a significant inhibitory effect on HAT activity of both pCAF and Gcn5, whereas it does not affect p300 and CBP HAT activity; decrease acetylation of histone H3 specifically at lysine 18 in a dose-dependent fashion, does not affect H3 histone methylation at lysines 9 and 4; induces cell-cycle perturbation and apoptosis in AML cells, induces differentiation in AML and neuroblastoma cells; impairs autophagy and reduces autophagosome turnover through an impairment of their degradation pathway.
WM-8014 (WM8014) is a highly potent, selective inhibitor of lysine acetyltransferase KAT6A with Kd of 5 nM and IC50 of 8 nM; WM-8014 is reversible competitor of acetyl coenzyme A and inhibits MYST-catalysed histone acetylation, also inhibits closely related KAT6B (IC50=28 nM), displays >10-fold selectivity over KAT7 and KAT5 (IC50=342 nM and 224 nM), shows no inhibition against KAT8, KAT2A, KAT2B, KAT3A and KAT3B; induces cell cycle exit and cellular senescence without causing DNA damage, reduces acetylation of specific histone lysine residues and changes in gene expression that resemble the genetic loss of KAT6A; selectively reduces liver volume in a zebrafish model of KRASG12V-driven hepatocellular overproliferation, robustly upregulate the cell cycle regulators Cdkn2a and Cdkn1a in hepatocytes.
WM-1119 (WM1119) is a highly potent, selective inhibitor of lysine acetyltransferase KAT6A with Kd of 2 nM, shows greate bioavailability and specificity for KAT6A than WM-8014; displays 1,100-fold and 250-fold selectivity over KAT5 and KAT7, respectively; causes cell cycle arrest in G1 and senescence phenotype similar to WM-8014; demonstrates growth inhibition assays in lymphoma cell line EMRK1184 (IC50=0.25 uM, 10-fold potency than WM-8014), increases levels of Cdkn2a and Cdkn2b mRNA and p16INK4a and p19ARF protein, as well as a delayed increase in Cdkn1a mRNA; arrests lymphoma growth in vivo without effect on haematocrit, erythrocytes or platelet numbers.
MC2884(MC 2884;MC-2884 ) is a novel hybrid, dual HAT/EZH2 inhibitor with IC50 of 3.27, 8.35 and 4.56 uM for CBP, KAT5 and p300, respectively; induces caspase- and mitochondrial-dependent cancer-selective apoptosis on a variety of cancers, accompanied by ROS production; displays anticancer action in both hematological and solid cancer in vivo models, induces apoptosis in aggressive cancers and in primary leukemic blasts, also synergizes with BCL2 inhibitors.
CPTH2 is a specific histone acetyltransferase inhibitor modulating Gcn5 network in vitro and in vivo, inhibits H3 acetylation and induces cell-cycle perturbation and apoptosis in U-937 cells; increases E1A CR3 transactivation of human adenovirus through inhibition of HAT GCN5, also reduces virus yield during infection; induces apoptosis and decreases the invasiveness of a ccRCC cell line through the inhibition of KAT3B.
Garcinol (Camboginol) is a potent, natural inhibitor of histone acetyltransferases (HATs) p300 (IC50=7 uM) and PCAF (IC50=5 uM) both in vitro and in vivo; downregulates various cell survival proteins including survivin, bcl-2, XIAP, and cFLIP, and induces bid cleavage, bax, and cytochrome c release, potentiates TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins; also siimulates neurogenesis and ex vivo expansion of human hematopoietic stem cells.
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